Chemotherapy is one of the most important treatments for breast cancer after operation. At present, the survival rate of patients has been effectively improved by referring to ER, PR, HER-2, Ki67, TNBC and other indicators. However, the study found that there are still about 30% recurrence and metastasis rates . It shows that the formulation of treatment plans based on the above pathological indicators may be incomplete, and there are other indicators for guiding treatment that can be excavated. In addition, there is still rise the survival rate of patients for adjustment in the formulation of treatment plans. Nowadays, more and more studies have found that the recurrence and metastasis of tumors are closely related to the DNA repair regulatory system related to drug resistance[22–24].
At present, not a few DNA repair genes, such as PARP1, XRCC1, 53BP1, ERCC1, have been found to be associated with the prognosis of breast cancer[25,26]. PARP1 promotes the expression of HIF-1α by activating nuclear factor-κB (NF-κB) and promotes the polarization of macrophages M2, leading to the up-regulation of tumor-related macrophages (TAMs), such as tumor necrosis factor-α (TNFα) and IL-6, thus promoting the proliferation, invasion and metastasis of tumor cells, promoting the formation of tumor microvessels and microlymphatics. And ERCC1 proteins can form heterodimers with DNA repair enzyme deficiency complementary gene (XPF) and perform functions by splicing at the 5'end of the damaged DNA single strand. Overexpression of ERCC1 proteins can lead to rapid repair of damaged DNA stagnating in G2/M, leading to resistance to cisplatin chemotherapeutics. In this study, nested case-control single factor analysis showed that protein levels of PARP1, XRCC1, 53BP1, ERCC1 recurrence and metastasis group was higher than control group. We further included that PARP1 (OR = 1.485, 95% CI:1.279–1.725), ERCC1 (OR = 1.181, 95% CI:1.032–1.353) as independent factors for recurrence and metastasis of breast cancer after operation. The results are similar to those of Sunada, S. et al. It shows that XRCC1 and 53BP1 become ineffective factors after excluding other confounding factors, while the high expression of PARP1 and ERCC1 in the course of chemotherapy will destroy the susceptibility of breast cancer cells, it can be make breast cancer cells less susceptible to chemotherapy, leading to resistance of breast cancer cells and even recurrence and metastasis of chemotherapy failure, which is affecting breast cancer. The independent prognostic factors of metastatic patients are not different from the existing studies.
In addition to the above genes related to breast cancer resistance, the prognosis-related DNA repair genes MSH2, MLH1, XRCC4 and XPA[31–33], which are frequently studied in the fields of colorectal cancer, lung cancer, prostate cancer and esophageal cancer, were also included in the study and analysis. Univariate analysis showed that MSH2, MLH1, XRCC4 and XPA in patients with recurrence and metastasis were higher than those without recurrence and metastasis. In binary logistic regression, only XRCC4 (OR = 1.419, 95% CI:1.217 ~ 1.656) was a risk factor for recurrence and metastasis of breast cancer, suggesting that XRCC4 was also associated with recurrence and metastasis of breast cancer after operation. The results of high expression of XRCC4 in esophageal and colorectal cancer suggest poor prognosis. It is possible that XRCC4 itself could form dimers and interact with BRCT domain (BRCA1-terminal, BRCT) at the C end of Ligase IV protein through its α spiral stem ring structure in the central region. Damage repair defects lead to accumulation of genetic damage, and then increase the susceptibility of the body to tumors, thereby increasing the risk of recurrence and metastasis of breast cancer patients.
However, the direct use of IHC score to analyze the recurrence and metastasis of breast cancer after surgery is of little significance. In order to further understand the role of PARP1, ERCC1 and XRCC4 in predicting the prognosis, metastasis and recurrence of breast cancer, we also studied the best cut-off value of PARP1, ERCC1 and XRCC4. The results showed that PARP1 (Cut-off Value = 6, Se = 75.23, Sp = 79.82), ERCC1 (Cut-off Value = 3, Se = 89.91, Sp = 47.71), XRCC4 (Cut-off Value = 6, Se = 78.90, Se = 79.82), suggesting that the risk of recurrence and metastasis increased at the scores of PARP1, ERCC1 and XRCC4 were higher than 6, 3, 6, respectively(PARP1: OR = 14.235, 95%CI:5.590 ~ 36.245; ERCC1: OR = 16.740, 95%CI:6.433 ~ 43.560; XRCC4: OR = 5.285, 95%CI:1.843 ~ 15.156), the risk of breast cancer recurrence and metastasis will increases. The sensitivity of PARP1, ERCC1 and XRCC4 single detection is between 75.23% ~ 89.91%, the specificity is between 47.71% ~ 79.82%, the Youden index is between 0.3761 ~ 0.5872, the sensitivity is qualified, but the specificity and Youden index are low. It indicates that the diagnostic value of individual tumor markers in the prognosis of breast cancer needs to be further improved. Due to PARP1, ERCC1 and XRCC4 belong to a part of DNA repair gene system, and the three proteins are positively correlated by correlation analysis (rPARP1−ERCC1=0.317; rPAPR1−XRCC4=0.329; rERCC1−XRCC4=0.377). These results suggest that there is an internal link among the three proteins and there is a certain synergy among them. So we combined PARP1, ERCC1 and XRCC4 to detect the prognosis of breast cancer. Joint diagnostic criteria: the high expression of a single indicator is judged as high, while the three indicators are simultaneously low and judged to be low. The results showed that after using the joint test, the specificity of diagnosis increased from 47.71–82.57%. The Youden index increased from 0.3761 to 0.7156. Sensitivity only decreased from 89.91–88.99%, a slight decrease, but the magnitude is very small. And in the binary logistic regression of breast cancer prognosis, the odds ratio of the combined indicators is as high as 50.914 (OR = 50.914, 95%CI:10.918 ~ 237.417). It can be seen that the combined detection of three DNA repair proteins has higher clinical diagnostic value than the single determination. It has been pointed out that PARP1 promotes the expression of HIF-1α by activating nuclear factor κB (NF-κB) and promotes the polarization of macrophages M2, leading to the up-regulation of tumor-related macrophages (TAMs), such as tumor necrosis factor alpha (TNFα) and IL-6, thus promoting the proliferation, invasion and metastasis of tumor cells, promoting the formation of tumor microvessels and microlymphatics. Overexpression of ERCC1 also up-regulates TNF-α, while XRCC4 in NHEJ pathway activates DNA-dependent protein kinase complex (DNA-PK), which is essential for the adhesion of monocytes to TNF-α treated endothelial cells. Other studies have found that in the process of tumorigenesis and development, most patients are accompanied by chronic inflammation, and the chronic protraction of inflammation affects the condition of tumors, leading to recurrence and metastasis of tumors. Tumor necrosis factor-α (TNFα) is closely related to the occurrence of cancer. The secretion of TNF-α cytokines in tumor microenvironment can accelerate the growth and spread of cancer cells. At the same time, it can make cancer cells bypass the impact of the immune system, promote the EMT process of cells, and cause recurrence and distant metastasis of cancer. These studies suggest that PARP1, ERCC1 and XRCC4 may act together on TNF-α to produce recurrence and metastasis of breast cancer. It can be seen that the combined detection of the three DNA repair proteins has higher clinical diagnostic value than the single determination, which is helpful for the early diagnosis of breast cancer prognosis.